(495a) Invited Talk: Using Molecular Simulations to Design Cationic Polymers for DNA Binding and Delivery

Gene delivery involves successful transfection of therapeutic DNA by a vector into target cells and expression of that genetic material. Viral vectors, while effective, can elicit harmful immunogenic responses, thus motivating ongoing research on non-viral transfection agents. Cationic polymers or polycations are a promising class of non-viral vectors due to their  low immugenic responses and low toxicity, and their ability to bind to the polyanionic DNA backbone to form a polycation-DNA complex (polyplex) that is then internalized in the target cell. Combinatorial approaches have generated many polycations with differing DNA transfection efficacies, but there is a need for general design guidelines that can relate the molecular features of the polycation to its DNA transfection efficiency. Using atomistic and coarse-grained molecular dynamics simulations of DNA and lysine based polycations with and without the nuclear localization sequence (PKKKRKV), we connect the thermodynamics of polycation-DNA binding to experimentally observed transfection efficiency of these polycations. In particular, our computational studies provide enthalpic and entropic contributions to DNA binding free energy, and the structure of the polycation-DNA complexes as a function of polycation chemistry and architecture.